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News U18

A new nanoconjugate blocks acute myeloid leukemia tumor cells without harming healthy ones

Researchers from NANBIOSIS U18 Nanotoxicology Unit at the Institut d’Investigació Biomèdica de Sant Pau (IIB Sant Pau) and NANBIOSIS U1 Protein Production Platform (PPP) at the Universitat Autònoma de Barcelona (UAB) toghether with researchers of Institut de Recerca contra la Leucèmia Josep Carreras (IJC) have demonstrated the efficacy of a new nanoconjugate, designed in house, that blocks dissemination of leukemic cells in animal models of acute myeloid leukemia. These results have been published in a high impact scientific journal in the field of oncology and hematology, Journal of Hematology and Oncology. Most of the experimental work has been performed in the nanotoxicology and protein production ICTS “NANBIOSIS” platforms from CIBER-BBN.

NANBIOSIS U1 PPP has advised and helped the researchers in the production of recombinant proteins, which has allowed to successfully explore the capacity of proteins from the human microbiome, that is, from bacteria and their bacteriogages, to generate, through genetic engineering, biocompatible nanomaterials and Non-immunogenic for potential use in human clinics, such as vehicles for drug delivery or regenerative medicine.

Acute myeloid leukemia (AML) is a heterogeneous disease which usual treatment is very aggressive and produces severe side effects to the patients. In order to reduce these adverse effects, the researchers have developed a nanomedicine that is specifically targeted to the tumor cells without damaging normal cells. This new protein nanoparticle is bound to a toxin, named Auristatin, which is between 10 and 100 times more potent than the drugs typically used in the clinic. In particular, this nanoconjugate is targeted only to the cells that express in their membrane a receptor called CXCR4, which is overexpressed in leukemic cells. Thus, this nanoparticle can only enter and deliver the toxin into the cells that express this receptor. It should be noted that CXCR4 is overexpressed in a large proportion of leukemic cells in patients with poor prognostic or refractory disease, so it could have a major clinical impact on these AML patients.

The researcher team led by Ramon Mangues, from IIB Sant Pau, Antonio Villaverde and Esther Vázquez, from UAB, all members of CIBER-BBN, has demonstrated that the nanoconjugate is able to internalize in the leukemic cells through the CXCR4 receptor and kill them. In addition, they have demonstrated the capacity of this nanoparticle to block dissemination of leukemic cells in a mouse model producing without any kind of associated toxicity or adverse effects. Thanks to its targeting to leukemic cells it could help AML patients that cannot be treated with current drugs because of their high toxicity, such as this experienced by elderly patients or patients with other non-favorable characteristics that exclude conventional treatment. Furthermore, the novel nanoparticle could be used to treat patients that have developed resistance to drugs or those that have experienced relapse, since their leukemic cells would likely have high expression of the CXCR4 receptor. Hence, there is a wide range of patients that could benefit of this new treatment, which could have  a major clinical impact if its effectiveness was confirmed in further clinical trials.

It is worth pointing out that the CXCR4 receptor is overexpressed in more than 20 different cancer types, which expression associates with poor prognosis. Therefore, this nanodrug could be evaluated in the near future as a possible treatment in other tumor types of high prevalence.

The intellectual property of this nanomedicine has been licensed to the SME biotech Nanoligent, which aim is continuing the so far successful access to public and private funds to complete the preclinical development to enter clinical trials in acute myeloid leukemia, before being tested in other cancer types.

Article of reference:

An Auristatin Nanoconjugate Targeting CXCR4+ Leukemic Cells Blocks Acute Myeloid Leukemia Dissemination. Victor Pallarès, Ugutz Unzueta, Aïda Falgàs, Laura Sánchez-García, Naroa Serna, Alberto Gallardo, Gordon A Morris, Lorena Alba-Castellón, Patricia Álamo, Jorge Sierra, Antonio Villaverde, Esther Vázquez, Isolda Casanova, Ramon Mangues. DOI: 10.1186/s13045-020-00863-9

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NANBIOSIS Scientists discover a promising effective alternative to reduse relapse rates in Diffuse Large B-cell Lymphoma Cells

Researchers of NANBIOSIS-ICTS Units from CIBER-BBN: U1 Protein Production Platform (PPP) at IBB-UAB, led by Antoni Villaverde and Unit 18 Nanotoxicology Unit at IBB-Hospital Sant Pau, led by Ramón Mangues, have demonstrated a potent T22-PE24-H6 antineoplastic effect, especially in blocking dissemination in a CXCR4+ DLBCL model without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients.

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK.

One of the major problems in the therapeutic strategies is the relapse rates. CXCR4-overexpressing cancer cells are good targets for therapy because of their association with dissemination and relapse in R-CHOP treated DLBCL patients but show a narrow therapeutic index due to their systemic toxicity wich generate the induction of severe side effects. NANBIOSIS researchers have developed a therapeutic nanostructured protein T22-PE24-H6 that incorporates exotoxin A from Pseudomonas aeruginosa, which selectively targets lymphoma cells because of its specific interaction with a highly overexpressed CXCR4 receptor (CXCR4+) in DLBCL, demonstrating a potent T22-PE24-H6 antineoplastic effect, without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients

The bioluminescent follow-up of cancer cells and toxicity studies has been performed in the ICTS Nanbiosis Platform, using its CIBER-BBN Nanotoxicology Unit and Protein production has been performed by the ICTS “NANBIOSIS”, more specifically by the Protein Production Platform of CIBER-BBN/ IBB

Article of reference:

Falgàs A, Pallarès V, Serna N, Sánchez-García L, Sierra J, Gallardo A, Alba-Castellón L, Álamo P, Unzueta U, Villaverde A, Vázquez E, Mangues R, Casanova I. Selective delivery of T22-PE24-H6 to CXCR4+ diffuse large B-cell lymphoma cells leads to wide therapeutic index in a disseminated mouse modelTheranostics 2020; 10(12):5169-5180. doi:10.7150/thno.43231. Available from http://www.thno.org/v10p5169.htm

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A new smart drug that finds and kills metastasis cells could be applied in 23 types of cancer

Researchers of two CIBER-BBN Units of the ICTS NANBIOSIS  U18 Nanotoxicology Unit at Hospital Sant Pau. and U1, Protein Production Platform (PPP), at the  Institute of Biotechnology and biomedicine of the Autonomous University of Barcelona (IBBUAB), led by Prof Ramón Mangues, have developed a new drug that selectively removes metastatic stem cells, inducing a powerful metastasis prevention effect.

Besides the participation of the “NANBIOSIS” ICTS Units
U1 Protein Production Platform where Protein production was partially performed and U18 Nantoxicology Unit where Biodistribution studies were performed, all in vivo experiments were performed by the Unit 20 In Vivo Experimental Platform of CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN)

The researchers have ceated inclusion bodies of amyloid and nanostructured fibers that, when administered subcutaneously in mice, release soluble cytotoxic nanoparticles continuously. These nanoparticles are carriers of the exotoxin of Pseudomonas aeruginosa that manages to maintain a stable concentration of this nanomedicine in the blood and tissues. Dr. Mangues explains that “this new pharmaceutical form of subcutaneous administration for sustained release allows high doses of this nanopharmaceutical to be administered, at prolonged intervals (weeks in mice and probably months in humans) without toxicity at the injection site or in normal tissues, while generating a powerful antimetastatic effect. Apart from being controlled-release systems, these nanoparticles incorporate a ligand that interacts with the receptor (CXCR4), present at high levels in the membrane of metastatic stem cells capable of generating metastases (CMM CXCR4 +). Once the new pharmaceutical form is administered subcutaneously in mice with metastatic colorectal cancer, this ligand directs each nanoparticle released by this structure to the tumor tissues, increasing their uptake, to specifically internalize in the CXCR4 + CMMs and induce their selective destruction. “This effect achieves a notable reduction in tumor size in the colon while blocking the development of lymph node, lung, liver and peritoneal metastases, without appreciable uptake or toxicity in non-tumor tissues” continous the researchers.

The researchers estimate that this new therapeutic strategy will have a high clinical impact by reducing the requirement of its hospital administration, which most antitumor drugs have, and blocking metastatic dissemination, responding to an unmet clinical need. On the other hand, this new pharmaceutical form, which combines sustained release with targeting to the CXCR4 receptor, could be used in the treatment of at least 23 types of cancer that also express high levels of this receptor in tumor cells.

The new therapy offers an answer to the urgent medical need to inhibit the development of metastases, which represents the leading cause of death in cancer patients. The selective destruction of tumor and metastatic cells increases the therapeutic index of nanomedicine, obtaining a potent antimetastatic effect without generating associated adverse effects, which differentiates it from most of the currently used antitumor drugs.

Article of reference

María Virtudes Céspedes, Olivia Cano‐Garrido, Patricia Álamo, Rita Sala, Alberto Gallardo, Naroa Serna, Aïda Falgàs, Eric Voltà‐Durán, Isolda Casanova, Alejandro Sánchez‐Chardi, Hèctor López‐Laguna, Laura Sánchez‐García, Julieta M. Sánchez, Ugutz Unzueta, Esther Vázquez, Ramón Mangues, Antonio Villaverde. Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci Adv.Mater.2019, 1907348


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NANBIOSIS research to fight cancer

Twenty years ago, the 4 February was declared World Cancer Day with the global challenge of cancer would not be forgotten. Since then, huge progress has been made to understand, prevent, diagnose, and treat cancer.

NANBIOSIS as an ICTS (Singular Scientific and Technical infrastructures) for biomedical research plays a very important role in the fight against cancer. Some examples of the work carried out during the last year, are bellow:

Unit 20 of NANBIOSIS  at VHIR, works in several proyects reletaed to cancer as  H2020-NoCanTher: magnetic nanoparticles against pancreatic cancer through the use of hyperthermia combined with conventional treatment. H2020-Target-4-Cancer: nanotherapy based on polymeric micelles directed against specific receptors of tumor stem cells in colorectal cancer. H2020-DiamStar: nanodiamonds directed against leukemia for the potentiation of chemotherapy. FET-OPEN EvoNano: in silico and tumor-tumor models for the prediction of PK / PD and tumor efficacy of antitumor nanomedicines against tumor stem cells.

The activities of U1 of Protein Production Platform (PPP) are also strongly committed with several projects devoted to develop new, more selective and more efficient antitumoral drugs, with antimetastatic effects.
oordinated action between units U1 of Protein Production Platform (PPP),
U18 of Nanotoxicology and U29 of Nucleic Acid Synthesis, shows promising results in development of nanopharmaceuticals with a high degree of efficacy for the treatment of metastases in colon cancer

Unit 6 of NANBIOSIS Biomaterial Processing and Nanostructuring Unit  is also working on a joined initiative between CIBER-BBN and CIBER-ONC to improve the current ex vivo immune cell expansion systems to help introduce immunotherapies such as the adoptive cell therapies, which have shown complete remissions of terminal cancer patients, to the clinics overcoming the limitation of having enough therapeutic cells with novel Nanobiomaterials. Researchers of Unit 6 and researchers of Laboratory of Translational Research in Child and Adolescent Cancer from the Vall d’Hebron Research Institute (VHIR), are working on a project financed by the Spanish Government and CIBER-BBN, for the development of a new nanomedicine for the treatment of high-risk neuroblastoma, one of the most frequent childhood cancers.

In our unit U26. NMR: Biomedical Applications II,  several studies for cancer biomarker discovery are being carried out. NMR studies on biofluids for the design of novel strategies for diagnosis support, easily transferable into the clinical practice, are being developed in biofluids in the context of cancer. Urine is one of the most easily obtainable biofluid and is a non-invasive source of biomarkers. Among these studies, we can mention the good discrimination achieved between urine from bladder cancer patients before surgery (cancer) and urine after surgery (free of cancer) and in the follow up of the disease, to monitor relapses

Some of the results of these researchs have been published in scientific magazines of high impact as for exemple;

Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer Alba Loras, Cristian Suárez-Cabrera, M. Carmen Martínez-Bisbal, Guillermo Quintás , Jesús M. Paramio, Ramón Martínez-Máñez,
Salvador Gil and José Luis Ruiz-Cerdá. Cancers 2019, 11, 686; doi:10.3390/cancers11050686

Nanostructured toxins for the selective destruction of drug-resistant human CXCR4+ colorectal cancer stem cells Naroa Serna, Patricia Álamo, Prashanthi Rameshef, Daria Vinokurovaef, LauraSánchez-García, Ugutz Unzueta, Alberto Gallardo, María  Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramón Mangues, Jan Paul Medema. . Journal of Controlled Release.  Volume 320, 96-104, 2020 https://doi.org/10.1016/j.jconrel.2020.01.019

Controlling self-assembling and tumor cell-targeting of protein-only nanoparticles through modular protein engineering Voltà-Durán, E., Cano-Garrido, O., Serna, N. et al. CSci. China Mater.63, 147–156 (2020). https://doi.org/10.1007/s40843-019-9582-9

Engineering Secretory Amyloids for Remote and Highly Selective Destruction of Metastatic Foci, María Virtudes Céspedes  Olivia Cano‐Garrido  Patricia Álamo  Rita Sala  Alberto Gallardo  Naroa Serna  Aïda Falgàs  Eric Voltà‐Durán  Isolda Casanova  Alejandro Sánchez‐Chardi  Hèctor López‐Laguna  Laura Sánchez‐García  Julieta M. Sánchez  Ugutz Unzueta  Esther Vázquez  Ramón Mangues  Antonio Villaverde . Advanced Materiasls Número de artículo: 1907348 , Dec. 2019 https://doi.org/10.1002/adma.201907348

Artificial Inclusion Bodies for Clinical Development Julieta M. Sánchez  Hèctor López‐Laguna  Patricia Álamo  Naroa Serna  Alejandro Sánchez‐Chardi  Verónica Nolan  Olivia Cano‐Garrido  Isolda Casanova  Ugutz Unzueta  Esther Vazquez  Ramon Mangues  Antonio Villaverde, Advanced Science. 2019 https://doi.org/10.1002/advs.201902420

Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells Mireia Pesarrodona, Laura Sánchez-García, Joaquin Seras-Franzoso, Alejandro Sánchez-Chardi, Ricardo Baltá-Foix, Patricia Cámara-Sánchez, Petra Gener,  José Juan Jara, Daniel Pulido, Naroa Serna, Simó Schwartz Jr. Miriam Royo, Antonio Villaverde, Ibane Abasolo, Esther Vazquez ACS Applied Materials & Interfaces DOI: 10.1021/acsami.9b15803  

Nanostructure Empowers Active Tumor Targeting in Ligand‐Based Molecular Delivery López‐Laguna, H., Sala, R., Sánchez, J. M., Álamo, P., Unzueta, U., Sánchez‐Chardi, A., Serna, N., Sánchez‐García, L., Voltà‐Durán, E., Mangues, R., Villaverde, A., Vázquez, E., . Part. Part. Syst. Charact. 2019, 36, 1900304. https://doi.org/10.1002/ppsc.201900304

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New nanocarrier for bio-imaging and drug-delivery applications

Researchers of CIBER-BBN and NANBIOSIS-ICTS (U6 Biomaterial Processing and Nanostructuring Unit at ICMAB-CSIC and U18 Nanotoxicology Unit at  Hospital de la Santa Creu i Sant Pau have developed a new nanocarrier for bio-imaging and drug-delivery applications

The new nanovesicle formulation is based on the quatsome architecture – which stands out due to the high colloidal stability and homogeneity in size – and has now been shown to be suitable for in vivo dosing.

Quatsomes are new non-liposomal lipid-based nanovesicles that have been developed by Nanomol group in recent years, and have been shown to be highly homogeneous and stable in different media for years. This colloidal stability involves important advantages for the development of pharmaceutical formulations and for guaranteeing the final product quality. Quatsomes are a promising nanocarrier for bio-imaging and drug-delivery applications, suitable for the encapsulation of both hydrophilic and hydrophobic molecules, easily functionalized with elements that favor the directionality towards therapeutic targets.

To facilitate their use in in vivo applications, Nanomol group has now developed a new Quatsome formulation, composed of cholesterol and myristalkonium chloride (MKC), the C14 homolog of benzalkonium chloride (BAK), the latter being extensively used as antimicrobial preservative in many ophthalmic and parenteral formulations on the EU and USA market. These novel MKC-Quatsomes have been synthesized in different media that are suitable for parenteral administration, in which they showed to be stable for at least 18 months. Moreover, vesicles remained stable in human serum for at least 24 hours.

In collaboration with the Oncogenesis and Antitumour Drug group of the Biomedical Research Institute of the Hospital de la Santa Creu i Sant Pau, these MKC-Quatsomes were tested in live mice bearing xenografted colorectal tumors. After intravenous injection of fluorescently labelled MKC-Quatsomes, biodistribution assays showed nanovesicle accumulation in tumors, liver, spleen, and kidneys, but not in any other organ. Importantly, MKC-Quatsomes were well-tolerated at the administered doses, and no histological alterations or toxicity was found in any of these organs. These new results suggest the applicability of quatsomes in therapeutic approaches that require systemic delivery.

NANOMOL group, Coordinator of NANBIOSIS U6 at ICMAB-CSIC and the Oncogenesis and Antitumor Drug group, coordinator NANBIOSIS U18 at Biomedical Research Institute (Hospital de la Santa Creu i Sant Pau) are members of Biomedical Research Networking center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) and have a wide expertise and recognized excellence in the synthesis, processing and study of molecular and polymeric materials and the study of their biomedical properties. NANOMOL is also a member of the technology transfer network TECNIO. ‘

Article of reference:

MKC-Quatsomes. A stable nanovesicle platform for bio-imaging and drug-delivery applications co-authored by Guillem Vargas-Nadal et al., Nanomedicine: Nanotechnology, Biology and Medicine, 24 (2020) 102136. https://doi.org/10.1016/j.nano.2019.102136

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A step forward for the design of multifunctional protein nanomaterials for cancer therapies

Researchers of NANBIOSIS Unit 1 and NANBIOSIS Unit 18, led by Prof Antoni Villaverde have published the article at the prestigious scintific magazine titled Collaborative membrane activity and receptor-dependent tumor cell targeting for precise nanoparticle delivery in CXCR4+ colorectal cancer

The researchers have shown that the combination of cell-penetrating and tumor cell-targeting peptides dramatically enhances precise tumor accumulation of protein-only nanoparticles intended for selective drug delivery, in mouse models of human colorectal cancer. This fact is a step forward for the rational design of multifunctional protein nanomaterials for improved cancer therapies.

Protein production has been partially performed by the  ICTS NANBIOSIS U1, Protein Production Platform and the nanoparticle size analysis by the U6  of NANBIOSIS Biomaterial Processing and Nanostructuring Unit. Biodistribution studies were performed by the U18 of the ICTS NANBIOSIS, Nanotoxicology Unit.

Article of reference:

Rita Sala, LauraSánchez-García, Naroa Serna, María Virtudes Céspedes, Isolda Casanova, Mònica Roldán, Alejandro Sánchez Chardig, Ugutz Unzueta, Esther Vázquez, Ramón Mangues, Antonio Villaverde. Collaborative membrane activity and receptor-dependent tumor cell targeting for precise nanoparticle delivery in CXCR4+ colorectal cancer. Acta Biomaterialia, 99, Pages 426-432. 2019,

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Why the poor biodistribution so far reached by tumor-targeted medicines?

Cell-selective targeting is expected to enhance effectiveness and minimize side effects of cytotoxic agents. Functionalization of drugs or drug nanoconjugates with specific cell ligands allows receptor-mediated selective cell delivery. However, it is unclear whether the incorporation of an efficient ligand into a drug vehicle is sufficient to ensure proper biodistribution upon systemic administration, and also at which extent biophysical properties of the vehicle may contribute to the accumulation in target tissues during active targeting. To approach this issue, structural robustness of self-assembling, protein-only nanoparticles targeted to the tumoral marker CXCR4 is compromised by reducing the number of histidine residues (from six to five) in a histidine-based architectonic tag. Thus, the structure of the resulting nanoparticles, but not of building blocks, is weakened. Upon intravenous injection in animal models of human CXCR4+ colorectal cancer, the administered material loses the ability to accumulate in tumor tissue, where it is only transiently found. It instead deposits in kidney and liver. Therefore, precise cell-targeted delivery requires not only the incorporation of a proper ligand that promotes receptor-mediated internalization, but also, unexpectedly, its maintenance of a stable multimeric nanostructure that ensures high ligand exposure and long residence time in tumor tissue.

Protein production has been partially performed by the  ICTS NANBIOSIS U1, Protein Production Platform and the nanoparticle size analysis by the U6  of NANBIOSIS Biomaterial Processing and Nanostructuring Unit. Biodistribution studies were performed by the U18 of the ICTS NANBIOSIS, Nanotoxicology Unit.

The concept presented by the authors of the present research might represent a convincing explanation of the poor biodistribution so far reached by tumor-targeted medicines, including antibody-drug conjugates. In addition to this, they offer a potential developmental roadmap for the improvement of these drugs, of high intrinsic therapeutic potential, to reach satisfactory efficiencies in the clinical context.

Hèctor López-Laguna, Rita Sala, Julieta M. Sánchez, Patricia Álamo, Ugutz Unzueta, Alejandro Sánchez-Chardi, Naroa Serna, Laura Sánchez-García, Eric Voltà-Durán, Ramón Mangues, Antonio Villaverde and Esther Vázquez. Nanostructure Empowers Active Tumor Targeting in Ligand-Based Molecular Delivery. Part. Part. Syst. Charact. 2019.

DOI: 10.1002/ppsc.201900304

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Artificial inclusion bodies for controlled drug release

Researchers from NANBIOSIS-CIBER-BBN have developed a new type of protein biomaterial that allows a continuous release over time of therapeutic proteins when administered subcutaneously in laboratory animals.

These results are the result of the stable scientific collaboration between the researchers of NANBIOSIS Units 1 Protein Production Platform (PPP)and 18 Nanotoxicology Unit, led by Toni Villaverde and Ramón Mangues at the Institute of Biotechnology and Biomedicine of the Autonomous University of Barcelona (IBB-UAB) and the Institut About the Hospital de Sant Pau and has had the participation of the Institute of Biological and Technological Research of the National University of Córdoba-CONICET, in Argentina

 “These structures, of a few micrometers in diameter, contain functional proteins that are released in a manner similar to the release of human hormones in the endocrine system,” says Antonio Villaverde. Ramón Mangues explains that “the new biomaterial mimics a common bacterial product in biotechnological processes called ‘inclusion bodies’, of pharmacological interest, which in this artificial version offers a wide range of therapeutic possibilities in the field of oncology and in any other field clinic that requires sustained release over time.” Researchers have used common enzymes in biotechnology as a model and a nanostructured bacterial toxin that targets metastatic cells of human colorectal cancer, which has been tested in animal models. “In this way we have managed to generate both immobilized catalysts and a new long-acting anti-tumor drug,” said the researchers responsible for the research.

The developed artificial protein granules, which had previously been proposed as ‘nanopills’ (tablets of therapeutic material on a nanoscopic scale), mimic bacterial inclusion bodies and offer enormous clinical potential in the field of vaccinology and as release systems Drug controlled.

“We have seen that natural inclusion bodies, administered as medicines, can generate unwanted immune responses due to the inevitable contamination with bacterial materials,” the researchers comment. However, in the new work, the development of artificial inclusion bodies with secretion capacity “avoids many of the regulatory problems associated with the potential development of bacterial nanopills, and offers a cross platform for obtaining functional components in cosmetics and in clinic” they add.

This work points to artificial inclusion bodies as a new exploitable category of biomaterials for biotechnological applications with a more simple manufacturing and clinical applications.

Reference article:
Julieta M. Sánchez, Hèctor López ‐ Laguna, Patricia Álamo, Naroa Serna, Alejandro Sánchez ‐ Chardi, Verónica Nolan, Olivia Cano ‐ Garrido, Isolda Casanova, Ugutz Unzueta, Esther Vazquez, Ramon Mangues, Antonio Villaverde Artificial Inclusion Bodies for Clinical Development

https: //doi.org/10.1002/advs.201902420

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A new method simple and efficient for the preparation of Oligonucleotide-protein conjugates

Oligonucleotide-protein conjugates have important applications in biomedicine. Four units of NANBIOSIS have collaborated to come across with more simple and efficient methods for the preparation of these conjugates.

In the publication of the research results, a new method is described in which a bifunctional linker is attached to thiol-oligonucleotide to generate a reactive intermediate that is used to link to the protein. Having similar conjugation efficacy compared with the classical method in which the bifunctional linker is attached first to the protein, this new approach produces significantly more active conjugates with higher batch to batch reproducibility. In a second approach, direct conjugation is proposed using oligonucleotides carrying carboxyl groups. These methodologies have been applied to prepare nanoconjugates of an engineered nanoparticle protein carrying a T22 peptide with affinity for the CXCR4 chemokine receptor and oligomers of the antiproliferative nucleotide 2′-deoxy-5-fluorouridine in a very efficient way. The protocols have potential uses for the functionalization of proteins, amino-containing polymers or amino-lipids in order to produce complex therapeutic nucleic acid delivery systems.

Protein production and DLS have been partially performed by the NANBIOSIS Units of CIBER-BBN  U1 Protein Production Platform (PPP) at IBB-UAB  and  U6 Biomaterial Processing and Nanostructuring Unit of CIBER-BBN and ICMAB-CSIC. Also, NANBIOSIS U18 of Nanotoxicology at the Hospital de la Santa Creu i Sant Pau has been used and the team of researcher counted with the NANBIOSIS expertise of U29 Oligonucleotide Synthesis Platform (OSP) at IQAC-CSIC

Article of reference:

Avino, Anna; Unzueta, Ugutz; Cespedes, Maria Virtudes; Casanova, Isolda; Vazquez, Esther; Villaverde, Antonio; Mangues, Ramon; Eritja, Ramon. Efficient bioactive oligonucleotide-protein conjugation for cell-targeted cancer therapy. CHEMISTRYOPEN 8, 3 (382-387), 2019

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A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

Researchers of NANBIOSIS Unit 1 and NANBIOSIS Unit 18,  led by Ramón Mangues, have published the article titled CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models .

One-third of diffuse large B-cell lymphoma patients are refractory to initial treatment or relapse after rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy. In these patients, CXCR4 overexpression (CXCR4+) associates with lower overall and disease-free survival. Nanomedicine pursues active targeting to selectively deliver antitumor agents to cancer cells, a novel approach that promises to revolutionize therapy by dramatically increasing drug concentration in target tumor cells. In the study carried out at NANBIOSIS ICTS the resarchers intravenously administered a liganded protein nanocarrier (T22-GFP-H6) targeting CXCR4+ lymphoma cells in mouse models to assess its selectivity as a nanocarrier, by measuring its tissue biodistribution in cancer and normal cells. No previous protein-based nanocarrier has been described to specifically target lymphoma cells. T22-GFP-H6 achieved a highly selective tumor uptake in a CXCR4+ lymphoma subcutaneous model, as detected by fluorescent emission. We demonstrated that tumor uptake was CXCR4- dependent because pretreatment with AMD3100, a CXCR4 antagonist, significantly reduced tumor uptake. Moreover, in contrast to CXCR4+ subcutaneous models, CXCR4- tumors did not accumulate the nanocarrier. Most importantly, after intravenous injection in a disseminated model, the nanocarrier accumulated and internalized in all clinically relevant organs affected by lymphoma cells, with negligible distribution to unaffected tissues. Finally, the researchers obtained antitumor effect without toxicity in a CXCR4+ lymphoma model by T22-DITOX-H6 administration, a nanoparticle incorporating a toxin with the same structure as the nanocarrier. Hence, the use of T22-GFP-H6 nanocarrier could be a good strategy to load and deliver drugs or toxins to treat specifically CXCR4-mediated refractory or relapsed diffuse large B-cell lymphoma without systemic toxicity.

The bioluminescent follow-up of cancer cells and nanoparticle biodistribution and toxicity studies has been performed in the ICTS NANBIOSIS, using its  unit 18 of Nanotechnology of CIBER-BBN and Hospital Sant Pau The Protein production has been partially performed by the Protein Production Platform (PPP) Unit 1 of ICTS NANBIOSIS of CIBER-BBN and IBB-UAB.

Article of reference:

Aïda Falgàs, Victor Pallarès, Ugutz Unzueta, María Virtudes Céspedes, Irene Arroyo-Solera, María José Moreno, Alberto Gallardo, María Antonia Mangues, Jorge Sierra, Antonio Villaverde, Esther Vázquez, Ramon Mangues, and Isolda Casanova.  A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models. Haematologica 2019


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